tbuckley/cabot-search huggingface dataset:
Abstract B008: UBXN2A targets Rictor-mTORC2 signaling pathway to inhibit colorectal cancer metastasis
Authors: Khosrow S. Rezvani
Journal: Cancer Research (2022)

Abstract The mTORC2 pathway plays a critical role in promoting tumor progression in human colorectal cancer (CRC). The regulatory mechanisms for this signaling pathway are only partially understood in CRC. We previously identified UBXN2A as a novel tumor suppressor protein in CRCs and hypothesized that UBXN2A suppresses the mTORC2 pathway, thereby inhibiting CRC growth and metastasis. We first used murine models to show that haploinsufficiency of UBXN2A significantly increases colon tumorigenesis. Induction of UBXN2A reduces AKT phosphorylation downstream of the mTORC2 pathway, which is essential for a plethora of cellular processes, including cell migration. Meanwhile, mTORC1 activities remain unchanged in the presence of UBXN2A. Mechanistic studies revealed that UBXN2A targets Rictor protein, a key component of the mTORC2 complex, for 26S proteasomal degradation. A set of genetic and pharmacological studies showed that UBXN2A regulates cell proliferation, apoptosis, migration, and colon cancer stem cells (CSCs) in CRC. CRC patients with a high level of UBXN2A have significantly better survival, and high-grade CRC tissues exhibit decreased UBXN2A protein expression. UBXN2A induction in tumor organoids suppresses the mTORC2 pathway. These findings provide new insights into the functions of a ubiquitin-like protein by inhibiting a dominant oncogenic pathway in CRC. Citation Format: Khosrow S. Rezvani. UBXN2A targets Rictor-mTORC2 signaling pathway to inhibit colorectal cancer metastasis [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer; 2022 Oct 1-4; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_1):Abstract nr B008.
Abstract IA004: Moving the needle: It is time for universal germline and somatic genetic testing in all colorectal cancer patients
Authors: Richard M. Goldberg
Journal: Cancer Research (2022)

Abstract The rapid evolution and commercialization of new techniques for analyzing DNA have extended our knowledge of inherited genetic abnormalities that can predispose a person to develop colorectal and other cancers. Concomitantly, the genetic fingerprinting of individual tumors has fueled the development of targeted therapies and informed their appropriate deployment for the management of individual patients. Recently, Cercek and colleagues at Memorial Sloan Kettering Cancer Center reported that all 14 patients with MSI-H rectal cancers treated in a clinical trial in the neoadjuvant setting with the PD-L1 inhibitor dostarlimab had complete remissions of their disease without chemotherapy, radiation, or surgery and those individuals are being followed to determine if, as hoped and expected, those remissions are durable (PMID:35660797). These insights have led and will continue to lead us to develop specific strategies to manage and minimize risk for affected individuals and their family members with inherited cancer susceptibility syndromes. They are also enabling us to decipher the practical value of the heterogeneity of colorectal cancers based upon the identification of inherited or acquired genetic abnormalities that drive the development and progression of an individual patient’s cancer. Now it is time to deploy germline and somatic genetic testing as a standard of care in the clinic, universally and equitably, for individualizing the assessment of inherited colorectal cancer susceptibility and for individualizing care in patients with colorectal cancer. Implementing this strategy will require resource allocation to ensure that health care teams and the patients that they care for both understand and derive the maximum possible benefit from implementing this new approach. Citation Format: Richard M. Goldberg. Moving the needle: It is time for universal germline and somatic genetic testing in all colorectal cancer patients [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer; 2022 Oct 1-4; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_1):Abstract nr IA004.
Abstract IA018: Microbiome and intestinal barriers in colon cancer
Authors: Jun Sun, Jilei Zhang, Yinglin Xia, Yong-Guo Zhang
Journal: Cancer Research (2022)

Abstract Multiple factors (e.g., risk genes, environmental triggers, immunity, and microbiome) contribute to the pathogenesis of colorectal cancer (CRC). The intestinal dysbiosis and disruption of barrier function are common manifestations of CRC. Vitamin D/Vitamin D receptor (VDR) is known to protects against dysbiosis and tumorigenesis. Considering the multiple functional roles of VDR in the development of cancer, it is important to dissect the mechanisms by which host factors contribute to the intestinal barrier function in protecting cells from tumorigenesis. Here, we reported that in human tissue, reduced VDR in the colon of CRC patients is associated with the reduced intestinal barrier and enhanced bacterial translocation to tumors. VDR deficiency in the intestinal epithelial cells led to the reduced thickness of mucus layer and enhanced penetration of microbiota into the epithelial cells. VDR was a transcriptional factor regulating the genes of some tight junction (TJ) Claudins. The positively correlated status of VDR and Claudins (e.g., Claudin- 5 and10) contribute to the altered intestinal permeability in tumorigenesis. In the intestinal epithelial VDR conditionally knockout VDR∆IEC mice and myeloid VDR deletion mice, dysbiosis and inflammatory cytokines in the VDR deficient context further altered TJ proteins and manipulated the barrier functions in the development of colon cancer. Furthermore, we found that mice with colonic adenomatous polyposis coli (APC) mutation reduced thickness of mucus layer and enhanced penetration of microbiota into the epithelial cells, thus enhancing tumorigenesis in the colon. Studies on host factor regulation of microbiome and barriers could be potentially applied to risk assessment, early detection, and prevention of colon cancer. These studies will provide an additional avenue to restore microbiome and barrier functions for risk assessment and prevention of CRC and other cancers. Citation Format: Jun Sun, Jilei Zhang, Yinglin Xia, Yong-Guo Zhang. Microbiome and intestinal barriers in colon cancer [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer; 2022 Oct 1-4; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_1):Abstract nr IA018.
Abstract IA016: Stem cells, therapy resistance and metastasis in colorectal cancer
Authors: Eduard Batlle
Journal: Cancer Research (2022)

Abstract The Cancer Stem Cell (CSC) concept states that tumor growth, analogous to the renewal of healthy tissues, is fueled by small numbers of dedicated stem cells. It provides attractive explanations for the clinical behavior of cancers and inspires treatment strategies that specifically target CSCs, the 'beating heart' of the tumor. Over the past years, an avalanche of studies has identified CSCs by expression of individual marker genes but the nature and features of these cells remain largely uncharacterized. As a case of example, LGR5 has been established as a bonafide marker of CSCs in gastrointestinal tumors. Many CRCs contain abundant LGR5+ cells yet clonal analysis suggests that only a small proportion of these cells function as CSCs. It is also known that many CRCs contain few or no LGR5+ cells, yet these tumors may still exhibit a hierarchical organization. Here, I will discuss our recent work on the functional states adopted by LGR5+ cells during CRC progression and the role of this cell population in chemotherapy resistance and metastatic dissemination. Citation Format: Eduard Batlle. Stem cells, therapy resistance and metastasis in colorectal cancer [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer; 2022 Oct 1-4; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_1):Abstract nr IA016.
Abstract IA008: Modeling immune-epithelial interactions in health and disease using human intestinal enteroid co-cultures
Authors: Nicholas C. Zachos
Journal: Cancer Research (2022)

Abstract Human intestinal enteroids derived from Lgr5+ actively dividing adult stem cells offer a relevant ex vivo system to study biological processes of the human small intestine and colon. While these primary cultures recreate cellular and functional features of the intestinal epithelium of the small intestine (enteroids) or colon (colonoids), they are limited by the lack of associated cell types, including immunological cells, nerves, stromal cells that help maintain tissue homeostasis and respond to external challenges. In the gut, innate immune cells interact with the epithelium by conducting lumial surveillance, support barrier function, and deploy effector functions in response to injury/damage. We have established a co-culture system of enteroid/colonoid monolayers and underlying macrophages and polymorphonuclear neutrophils to recapitulate the cellular framework of the human intestinal epithelial niche. Human intestinal enteroids can generated from biopsies or resected tissue from any segment of the human intestine/colon and maintained in long-term cultures in a basement membrane-rich matrix supplemented with growth factor-conditioned media necessary to maintain intestinal stem cell homeostasis. Immune cells are isolated from fresh human whole blood or frozen peripheral blood mononuclear cells (PBMC) and co-cultured with human intestinal enteroids/colonoids grown as confluent monolayers on permeable supports (e.g., Transwells). This configuration allows for controlled access to the apical side of the epithelium to mimic the gut luminal environment as well as the basolateral side occupied by immune cells to mimic the mucosal environment. Enteroid-immune co-cultures enable multiple outcome measures, including transepithelial resistance, production of cytokines/chemokines, phenotypic analysis of immune cells, tissue immunofluorescence imaging, protein or mRNA expression, antigen or microbe uptake, and other cellular functions. Citation Format: Nicholas C. Zachos. Modeling immune-epithelial interactions in health and disease using human intestinal enteroid co-cultures [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer; 2022 Oct 1-4; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_1):Abstract nr IA008.
Abstract PR001: The use of risk prediction for patients with abnormal fecal testing (FIT) to prioritize patient navigation
Authors: Amanda F. Petrik
Journal: Cancer Research (2022)

Abstract Context: “Precision delivery involves using an individual’s electronic health data to predict risk and personalize care to substantially improve value” (Parikh). Rates of completion of the follow-up colonoscopy following an abnormal FIT are low in community clinics. Tools like predictive analytics can be used for population management and more precise delivery of care to those who need it the most. Objective: We describe 3 studies use of predictive analytics after abnormal FIT testing to prioritize patient navigation to complete subsequent colonoscopies. Study design and analysis: The Strategies and Opportunities to Prevent Colorectal Cancer (STOP CRC) trial developed an initial risk prediction model identifying patients unlikely to complete a follow-up colonoscopy on their own. Kaiser Permanente Northwest (KPNW) then redeveloped the model for use with Navigation. The Predicting and Addressing Colonoscopy Non-adherence in Community Settings (PRECISE) study then redeveloped the model for use with Navigation in a large Federally Qualified Health Center (FQHC). Results: The STOP CRC model included 8 variables, 1596 patients had an abnormal FIT result, 34.8% had a recorded colonoscopy within 6 months. The model shows an adequate separation of patients across risk levels for non-adherence to follow-up colonoscopy (bootstrap-corrected C-statistic &amp;gt; 0.63). The KPNW model included 14 variables, and the performance of the model was adequate with a bootstrap corrected C-statistic of 0.65. The PRECISE model included 12 variables and a bootstrap corrected C-statistic of 0.58. Here we will describe each of the models and the differences in the application of the models. Conclusions: Risk prediction can be used to identify patients unlikely to complete colonoscopies, and as a population management tool to tailor interventions to specific populations. Tailoring interventions can save money, and increase patient satisfaction. Citation Format: Amanda F. Petrik. The use of risk prediction for patients with abnormal fecal testing (FIT) to prioritize patient navigation [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer; 2022 Oct 1-4; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_1):Abstract nr PR001.
Abstract A023: Influence of pre-diagnosis obesity and post-diagnosis aspirin use on survival from stage IV colorectal cancer
Authors: Jennifer S. Davis, Janelle C. Chavez, Melissa Kok, Yazmin San Miguel, Hwa Young Lee, Henry Henderson, Michael J. Overman, Van Karlyle Morris, Bryan Kee, David Fogelman, Shailesh M. Advani, Benny Johnson, Christine Parseghian, John Paul Shen, Arvind Dasari, Kenna R. Shaw, Eduardo Vilar, Kanwal P. Raghav, Imad Shureiqi, Robert A. Wolff, Funda Meric-Bernstam, Dipen Maru, David G. Menter, Scott Kopetz, Shine Chang
Journal: Cancer Research (2022)

Abstract Background: The relationship between obesity and colorectal cancer (CRC) outcome is poorly understood in late-stage patients. Increased body mass may negate aspirin use for cancer prevention, but the influence of body mass index (BMI) on post-diagnosis aspirin use is unclear. This study aims to evaluate impacts of pre-diagnosis BMI and post-diagnosis aspirin use on overall survival in late-stage CRC patients on the Assessment of Targeted Therapies Against Colorectal Cancer (ATTACC) clinical protocol. Methods: Patients with metastatic or treatment refractory disease were consented on the ATTACC protocol at MD Anderson Cancer Center and invited to complete a survey on risk factors relevant to CRC etiology. Using survey data, BMI was calculated from the decade prior to initial CRC diagnosis for 656 patients. Survival was measured from stage IV diagnosis until death or last follow-up. Cox Proportional Hazards models were constructed to estimate associations of pre-diagnosis obesity and post-diagnosis aspirin use with overall survival. Results: Controlling for age, sex, race, stage at initial diagnosis, and weight change between pre-diagnosis and survey date, patients with pre-diagnosis obesity had significantly higher likelihood of death (HR 1.45, 95% CI: 1.11, 1.91) compared to those with normal pre-diagnosis BMI. Further, only patients with normal weight pre-diagnosis experienced a survival benefit with post-diagnosis aspirin use (HR 0.59, 95% CI: 0.39, 0.90). Conclusions: Our findings suggest potentially differential tumor development resulting from the long-term physiologic host environment, here obesity. Confirmation and further evaluation are needed to determine whether pre-diagnosis BMI may predict benefit from post-diagnosis aspirin use. Citation Format: Jennifer S. Davis, Janelle C. Chavez, Melissa Kok, Yazmin San Miguel, Hwa Young Lee, Henry Henderson, Michael J. Overman, Van Karlyle Morris, Bryan Kee, David Fogelman, Shailesh M. Advani, Benny Johnson, Christine Parseghian, John Paul Shen, Arvind Dasari, Kenna R. Shaw, Eduardo Vilar, Kanwal P. Raghav, Imad Shureiqi, Robert A. Wolff, Funda Meric-Bernstam, Dipen Maru, David G. Menter, Scott Kopetz, Shine Chang. Influence of pre-diagnosis obesity and post-diagnosis aspirin use on survival from stage IV colorectal cancer [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer; 2022 Oct 1-4; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_1):Abstract nr A023.
Abstract B003: Cross-reacting antigens between the intestinal microbiome and tumor neoantigen are associated with immune checkpoint inhibitor response in a gastrointestinal tumor cohort
Authors: Ravin Poudel, Die Dai, Fang Li, Xiaochen Yin, Yan Kou, Antonio L. C. Gomes
Journal: Cancer Research (2022)

Abstract Background: Immune checkpoint inhibitor (ICI) is a revolutionary therapy that promotes the activation of effector T cells against tumors. Despite the potential for long-term benefit, a large proportion of patients does not respond to ICI therapy. One reason for this heterogenic response is due to the high variability in the intestinal microbiota among different patients. The abundance of certain bacteria has been associated with different responses and fecal meta transplant from responding donors was shown to rescue a beneficial phenotype in refractory patients. The presence of cross-reactive antigens (CRAgs) between the gut microbiome and tumor neoantigens has been proposed as a potential mechanism that could link the intestinal microbiota with ICI response. However, empirical evidence of CRAg’s role in ICI therapy is limited to a few studies. Methods: We investigated ICI response in a cohort of 22 stage IV gastrointestinal (GI) tumor patients in which whole-exome and gut metagenomic sequencing data were available. This cohort included patients with gastric cancer (n=11), esophageal carcinoma (n=6), and colon cancer (n=5). For each patient, we characterized the tumor neoantigen load based on epitopes that show high affinity and presentability in HLA molecules. Neoantigens were matched to the intestinal microbiome to identify corresponding CRAgs. CRAg quality, which ranks CRAgs according to their immunogenic potential, was defined based on matches in immunogenic protein or epitope databases. Results: We found the total number of CRAgs varied per tumor type, with a higher abundance in colon cancer (median µ=619) followed by esophageal (µ =287.5) and gastric (µ = 243). Interestingly, colon cancer patients showed a better progression-free survival (PFS) curve followed by esophageal and gastric cancer patients, respectively. We also observed that CRAg load was better associated with longer PFS (p=.03) than neoantigen load (p=0.07). Moreover, CRAg’s quality showed to be an important predictor of PFS. Patients with a high proportion of CRAgs matching at least one of the quality databases showed better PFS (p=0.02). Further, a taxa-specific analysis indicated that commensal CRAgs load was a better predictor of PFS (p&amp;lt;0.008) than relative abundance. Altogether, our work supports a mechanistic link between the microbiome, neoantigens, and immuno-therapy. Citation Format: Ravin Poudel, Die Dai, Fang Li, Xiaochen Yin, Yan Kou, Antonio L. C. Gomes. Cross-reacting antigens between the intestinal microbiome and tumor neoantigen are associated with immune checkpoint inhibitor response in a gastrointestinal tumor cohort [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer; 2022 Oct 1-4; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_1):Abstract nr B003.
Abstract IA028: Circulating tumor DNA in the management for colorectal cancer: Are we there yet?
Authors: Van Karlyle Morris
Journal: Cancer Research (2022)

Abstract Assessment of circulating tumor DNA represents a highly specific and highly sensitive "liquid biopsy" methodology to detect the presence (or absence) of microscopic disease for patients with colorectal cancer. With performance of available circulating tumor DNA assays rapidly evolving, the clinical and scientific applications subsequently continue to expand. Data generated by circulating tumor DNA/liquid biopsies has translated into the clinical management of colorectal cancer as a prognostic biomarker forecasting disease recurrence after resection and also for quantitative and qualitative characterization of treatment response in patients with metastatic colorectal cancer. To date, evidence of utility of circulating tumor DNA as a predictive biomarker for systemic treatment remains missing and illustrates a critical gap in knowledge. To address this unmet need, currently assessment of patients' blood specimens can provide critical cancer-specific insight into the dynamics not only of the colorectal cancer genome but also of the epigenome and transcriptome. Clinical trials are evaluating circulating tumor DNA as a novel approach to identifying micrometastatic colorectal cancer as a biologically distinct pathology that differs from larger, clinically detectable disease, with the intention for development of unique, targeted approaches which may ultimately improve outcomes for patients with colorectal cancer. Citation Format: Van Karlyle Morris. Circulating tumor DNA in the management for colorectal cancer: Are we there yet? [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer; 2022 Oct 1-4; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_1):Abstract nr IA028.
Abstract A028: Multi-modal digital pathology by sequential acquisition and joint analysis of highly multiplexed immunofluorescence and hematoxylin and eosin images
Authors: Jia-Ren Lin, Yu-An Chen, Daniel Campton, Jeremy Cooper, Shannon Coy, Clarence Yapp, Erin McCarty, Keith L. Ligon, Steven Reese, Tad George, Sandro Santagata, Peter Sorger
Journal: Cancer Research (2022)

Abstract Histopathology using Hematoxylin and Eosin (H&amp;E) stained tissue sections plays a central role in the diagnosis and staging of diseases. The transition to digital H&amp;E pathology affords an opportunity for integration with recently developed, highly multiplexed tissue imaging methods. Here we describe an approach (and instrument) for collecting and analyzing H&amp;E and high-plex immunofluorescence (IF) images from the same cells at subcellular-resolution in a whole-slide format suitable for translational and clinical research and eventual deployment in a diagnostic setting. IF and H&amp;E images provide highly complementary information for analysis by human experts and machine learning algorithms. Using images of 40 human colorectal cancer resections, we demonstrate the automated generation and ranking of computational models, based either on immune infiltration or tumor-intrinsic features, that are highly predictive of progression-free survival. When these models are combined, a hazard ratio of ~0.045 can be achieved, suggesting the potential of integrated H&amp;E and high-plex imaging in the generation of high performance prognostic biomarkers. Citation Format: Jia-Ren Lin, Yu-An Chen, Daniel Campton, Jeremy Cooper, Shannon Coy, Clarence Yapp, Erin McCarty, Keith L. Ligon, Steven Reese, Tad George, Sandro Santagata, Peter Sorger. Multi-modal digital pathology by sequential acquisition and joint analysis of highly multiplexed immunofluorescence and hematoxylin and eosin images [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer; 2022 Oct 1-4; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_1):Abstract nr A028.